The candidate is a gynecologic oncologist with a commitment to a career in basic science and translational research. The University of Washington has a strong clinical cancer program, an established gynecologic cancer tissue bank, and a renowned research program in genomics and medical genetics. Under the guidance of Mary-Claire King, Ph.D., the candidate will use these institutional resources to gain advanced training in genetics laboratory research while completing the proposed project. She will participate in the didactic activities for fellows in the Division of Medical Genetics. Ovarian cancer has the highest mortality among gynecologic cancers, and current screening strategies are inadequate for application to the general population. This study will pursue the goal of identifying novel molecular markers in ovarian cancer using two strategies: 1. A gene-based strategy based on the hypothesis that BRCA1 is important in the development of sporadic ovarian cancer and that BRCA1 and related genes are aberrantly regulated early in the development of ovarian cancer. 2. A marker-based strategy based on the hypothesis that tumor-specific changes identified in mitochondrial or nuclear DNA are identifiable in DNA obtained from peritoneal fluid or from patient sera or plasma and can be used as prognostic or diagnostic tools. In both strategies, molecular findings will be correlated to clinical variables and patient outcomes to identify those molecular markers with potential utility as a prognostic or diagnostic tool.
Specific Aim 1. In ovarian cancers, evaluate expression of BRCA1 and other proteins that may interact with BRCA1 including Id4, CTCF, and ATM, correlating protein expression with clinical outcomes in both hereditary and sporadic ovarian cancer.
Specific Aim 2. Evaluate promoter methylation of genes in ovarian cancer including BRCA1, MLH1, THBS1, CDH1, Cyclin D2, ERalpha and ERbeta. Assess tumor-specific methylation in DNA from patient sera, plasma and peritoneal fluid, correlating these findings with clinical variables and outcomes.
Specific Aim 3. Identify the frequency of mitochondrial mutations or variants in ovarian cancers in comparison to matched normal DNA. Assess tumor-specific mitochondrial mutations in DNA from patient sera or plasma and peritoneal fluid, and correlate the presence of the mutations with clinical outcomes. Preliminary data indicate the feasibility of all three specific alms. These studies may identify new prognostic or diagnostic markers in ovarian cancer. Such markers could then be tested in prospective trials to determine their clinical utility.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08CA096610-01
Application #
6507573
Study Section
Subcommittee G - Education (NCI)
Program Officer
Eckstein, David J
Project Start
2002-09-27
Project End
2007-08-31
Budget Start
2002-09-27
Budget End
2003-08-31
Support Year
1
Fiscal Year
2002
Total Cost
$131,463
Indirect Cost
Name
University of Washington
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Swisher, Elizabeth M; Gonzalez, Rachel M; Taniguchi, Toshiyasu et al. (2009) Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas. Mol Cancer 8:48
Sakai, Wataru; Swisher, Elizabeth M; Jacquemont, CĂ©line et al. (2009) Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma. Cancer Res 69:6381-6
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Swisher, Elizabeth M; Sakai, Wataru; Karlan, Beth Y et al. (2008) Secondary BRCA1 mutations in BRCA1-mutated ovarian carcinomas with platinum resistance. Cancer Res 68:2581-6
Sakai, Wataru; Swisher, Elizabeth M; Karlan, Beth Y et al. (2008) Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature 451:1116-20
Willner, Julia; Wurz, Kaitlyn; Allison, Kimberly H et al. (2007) Alternate molecular genetic pathways in ovarian carcinomas of common histological types. Hum Pathol 38:607-13
Galic, Vijaya; Willner, Julia; Wollan, Melissa et al. (2007) Common polymorphisms in TP53 and MDM2 and the relationship to TP53 mutations and clinical outcomes in women with ovarian and peritoneal carcinomas. Genes Chromosomes Cancer 46:239-47
Lamb, Julie D; Garcia, Rochelle L; Goff, Barbara A et al. (2006) Predictors of occult neoplasia in women undergoing risk-reducing salpingo-oophorectomy. Am J Obstet Gynecol 194:1702-9
Garg, Ruchi; Wollan, Melissa; Galic, Vijaya et al. (2006) Common polymorphism in interleukin 6 influences survival of women with ovarian and peritoneal carcinoma. Gynecol Oncol 103:793-6

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